Minute particles emanating from either ultra high molecular weight polyethylene (“UHMWPE”) interfaces or polymethylmethacrylate (“PMMA”) cement cause an inflammatory immune response resulting in osteolysis (i.e., dissolution or degeneration of bone tissue). Osteolysis is believed to be a primary causes of implant revision in hip and knee implants. It is believed the method of the present invention is applicable to other implants that are susceptible to the above-described mechanism of inflammatory immune response resulting in osteolysis including other artificial joints such as spinal discs.
Conventional means of treating osteolysis include: a) providing smoother wear surfaces; b) providing more wear resistant UHMWPE; c) a continuous infusion pump or gene technology as a means of providing IL-10; and d) prosthetic revision surgery.
Some of the osteolysis literature has suggested that the complexing of polyethylene and IgG leads to a Th1-type pro-inflammatory response. It has been suggested in the literature that certain implanted polymers such as silicone may provide an adjuvant-like activity to native macromolecules, which adhere to hydrophobic surfaces and subsequently become immunogenic. Kossovsky, CRC Crit. Rev. Biocompat. 3, 53-85, 1987. In regards to UWMWPE, Wooley, JBJS, 81-a (5) May 1999, 616-623, has suggested that most hip joint prosthesis patients express antibodies that are reactive with the proteins bound to polyethylene and that type I collagen is a major antigenic target in these patients. Wooley reported that type I collagen was often found bound to polyethylene particles, and further suggested that the implantation of the biomaterial, followed by deposition of collagen, may contribute to increased levels of antibodies. Wooley then hypothesizes that immunoglobulin complexed with polyethylene may fix complement and that the complement cascade may in turn attract inflammatory cells to the polyethylene surface. Stuart, J. Exp. Med., 155, January 1982, 1-16, reports that IgG anticollagen antibodies can cause arthritis. Bosetti, Biomaterials, 24, 2003, 1419-26 reports the adsorption of pro-inflammatory IgG upon the surface of UHMWPE.
Accordingly, the literature suggested not only that the binding of collagen to polyethylene but also the binding of IgG to polyethylene may drive a pro-inflammatory response.
Another portion of the osteolysis literature has suggested that the complexation of polyethylene and IgG leads to a Th2-type anti-inflammatory response. For example, Anderson, J. Imunology, 2002, 168:3697-3701, (“Anderson I”) reports that whereas use of macrophages as antigen-presenting cells (APCs) resulted in a strong polarized T cell response predominated by Th1 cytokines, when the antigen was targeted to FCχ receptors on these APCs, the T cell response was reversed and biased toward a Th2-type response. Anderson I concludes that when APCs encounter immune complexes, their cytokine production is modulated to create a cytokine microenvironment which preferentially induces a Th2-like response dominated by IL-4, and that IgG can override innate signals generated by microbial products and drive Th2-like immune responses. Anderson, J. Endotoxin Research 8(6), 2002, 477-481, (“Anderson II”) reports that cells exposed to IgG immune complexes generate large amounts of IL-10, and as a result exert a potent anti-inflammatory effect on the immune response. Anderson II further reports that the ligation of FCχ receptors on activated macrophages by antigen—IgG complexes induced T cells to produce IL-4, which in turn induced B cells to produce IgG1 (a Th2 IgG) in response to that antigen. Anderson II concludes that the mechanism by which IgG can influence immune deviation is by changing the phenotype of the APC, inducing the production of IL-10 instead of IL-12.
Accordingly, the literature suggests that the production of UHMWPE wear debris may drive both Th1 and Th2 responses. The suggestion of a mixed response is consistent with the reporting of Arora, JBMR 64A: 693-697, 2003. Arora examined the specific role of lymphocytes in the Th1 and Th2 subsets in osteolysis and aseptic loosening and found significant numbers of T cells and Th1 and Th2 immune cytokines, and concluded there was a possibility of an immune response at the prosthetic interface.
Since it is likely that the production of UHMWPE wear debris invokes a mixed type immune response involving both Th1 and Th2 cells and both pro- and anti-inflammatory cytokines, the present inventors believe that the presence of a significant Th1 component in the immune response is responsible for the induction of osteolysis.
There have been a number of reports disclosing the beneficial effects of IL-10 upon osteolysis. For example, Pollice J. Orthop. Res. 1998 November 16(6) 697-704 discloses that IL-10 inhibits inflammatory cytokine synthesis by monocytes stimulated with titanium particles. Trindade, Biomaterials 22(2001) 2067-73 discloses that IL-10 inhibits PMMA induced IL-6 and TNF-a release by human monocytes/macrophages in vitro. Goodman, JBMR, 65A:43-50, 2003 used a small infusion pump to continuously provide IL-10 to a site contaminated with UHMWPE particles and found that local infusion of immune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis. Carmody, Arthritis & Rheumatism, 46(5) May 2002 pp. 1298-1308 teaches viral IL-10 gene inhibition of inflammation, osteoclastogenesis and bone resorption in response to titanium particles.
It is an object of the present invention to treat osteolysis resulting from orthopedic implants so that revision surgery is not needed or is significantly delayed.